Research

The overall goal of my research is to identify new therapeutic strategies targeting
inflammatory processes. We are particularly interested in studying the cellular and
molecular events taking place in allergic airway and skin inflammatory diseases, such
as asthma and atopic dermatitis, and their exacerbations, including life-threatening
anaphylaxis.

The major culprit of allergy-driven diseases is the mast cell. We are investigating
many aspects of human and rodent mast cell biology from ontogeny to survival to phenotype
plasticity and functions. To this end, we are using in vitro and in vivo pharmacological,
molecular and genetic approaches. We recently discovered that a potently bioactive
sphingolipid metabolite sphingosine-1-phosphate (S1P) can be released from mast cells,
in addition to a variety of mediators such as histamine, cytokines, chemokines and
other lipid components, upon allergic stimulation and act on its own receptors on
mast cells supporting an autocrine inflammatory amplification loop.

In particular,

We propose to further examine the roles of S1P, the kinases that produce it and its
receptors in regulating mast cell development and functions. We have established the
relevance of S1P and its receptor S1PR2 inacuteexacerbation of systemic allergic reaction called anaphylaxis. Our current research
aims to assess the role of mast cells and S1P as key coordinators of multiple disease
processes leading to the establishment of chronic allergic inflammation and tissue
remodeling for which there is, presently, no cure.

Mast cell proteases determine their responsiveness to stimuli and drug sensitivity.
We are studying how chymase expression is regulated by IL-6 and its correlation with
the surface expression of the receptor for anaphylatoxin C5a, CD88, generated upon
complement activation. Moreover, chymase expression correlates with enhanced survival,
another area under investigation. Interestingly, we found that S1P enhances chymase
and CD88 expression in developing human mast cells, which display a hyperresponsive
phenotype. Therefore S1P could be an important player in regulating chymase, CD88
expression and mast cell responsiveness to stimuli.

Bone marrow, blood, lung and skin eosinophilia, or increased numbers of eosinophils,
is frequently observed in patients with inflammatory disorders and a hallmark of asthma
and atopic dermatitis. IL-5 is the most selective cytokine related to eosinophil differentiation
as the expression of its receptor is limited to eosinophils and basophils. Stimulation
of human cord blood-derived progenitor cells with IL-3, IL-5 and GM-CSF leads to the
exclusive upregulation of the IL-5R alpha subunit, a pivotal step in eosinophil lineage
commitment. However, the unresponsiveness to all three cytokines in mice does not
prevent the development of eosinophils, suggesting the intervention of other factors
in eosinopoiesis. We are investigating how the mast cell/S1P/eosinophil triad could
also constitute a functional unit to sustain chronic inflammation of the lungs and
skin.

Our proposed studies will lead to a better understanding of the mechanisms underlying
persistent inflammation and facilitate mechanistically tailored therapies targeting
local regulatory pathways in inflammation with a central role for mast cells.